Cutaneous head and neck melanoma: the old and the new.
ABSTRACT The incidence rate of malignant melanoma has shown a rapid worldwide rise in recent years. The staging and management of head and neck melanoma presents some unique challenges. Surgery remains the cornerstone of treatment, while sentinel node biopsy is the most accurate staging modality for regional disease. The complex regional anatomy and lymphovascular drainage of this region may account for the increased biologic aggressiveness and treatment challenges of this disease. Improved understanding of the radiobiology of melanoma has resulted in new adjuvant radiotherapy approaches, yielding improved control rates. The treatment outcomes of metastatic head and neck melanoma remain disappointing but important progress has been made in the understanding of melanoma biology.
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ABSTRACT: Interferon alpha (IFNα) is widely used for treatment of melanoma and certain other malignancies. This cytokine as well as the related IFNβ exerts potent anti-tumorigenic effects; however, their efficacy in patients is often suboptimal. Here, we report that inflammatory signaling impedes the effects of IFNα/β. Melanoma cells can secrete pro-inflammatory cytokines that inhibit cellular responses to IFNα/β via activating the ligand-independent pathway for the phosphorylation and subsequent ubiquitination and accelerated degradation of the IFNAR1 chain of type I IFN receptor. Catalytic activity of the p38 protein kinase was required for IFNAR1 downregulation and inhibition of IFNα/β signaling induced by proinflammatory cytokines such as interleukin 1 (IL-1). Activation of p38 kinase inversely correlated with protein levels of IFNAR1 in clinical melanoma specimens. Inhibition of p38 kinase augmented the inhibitory effects of IFNα/β on cell viability and growth in vitro and in vivo. The roles of inflammation and p38 protein kinase in regulating cellular responses to IFNα/β in normal and tumor cells are discussed.Oncogene 06/2011; 31(2):161-72. · 7.36 Impact Factor
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ABSTRACT: A b s t r a c t Cerebral ischemia/reperfusion injury induces alterations of the neurochemical conditions in the vulnerable regi- ons of the brain. The role of calcium in the process of neuronal injury with special attention to participation of reactive oxygen/nitrogen (RO(N)S) species will be discussed. An excess amount of RO(N)S is up-regulated in res- ponse to ischemic stress and participates in neuronal apoptosis by several processes. Paper is focused on cellular and molecular mechanisms of intracellular calcium stores with special attention to neuronal damage induced by cerebral ischemia/reperfusion. Acute in vivo ischemia alters both the expression, function and kinetic parameters of Ca2+ transporters and the physical membrane environment. Experimental results present evidence that endoplasmic reticulum (ER) is the site of complex processes such as calcium stora- ge, synthesis and folding of proteins and cell response to stress. ER function is impaired in ischemia/reperfusion injury which in turn induce calcium store depletion and conserved stress responses linked with delayed neuronal death. Understanding the mechanisms leading to ischemia-induced disturbation of calcium stores and the ER dysfunction may lead to recognition of neuronal protection strategies and suggestions for further studies on the development of novel prophylactic/therapeutics for neuronal apoptosis-related diseases.